Tips, tricks and know how for treating sleep disorders in neurology Suzanne Stevens, MD, MS, D-ABSM Clinical Assistant Professor, Department of Neurology Director, Sleep Medicine Clinic Restless Leg Syndrome (RLS) = Willis Ekbom Disease (WED) Reasons for the name change The name Willis-Ekbom disease: 1.Eliminates incorrect descriptorsthe condition often involves parts of the body other than legs 2.Promotes cross-cultural ease of use 3.Responds to trivialization of the disease 4.Acknowledges the first known description by Sir Thomas Willis in 1672 and the first detailed clinical description by Dr. Karl Axel Ekbom in 1945. 17th Century Description of RLS by Sir Thomas Willis considered restless legs. Although Willis syndrome was thought to be the release of animal humors into the nerves of the legs, he offered an excellent observation: Wherefore to some, when being abed they betake themselves to sleep, presently in the arms and legs, leapings and contractions of the tendons, and so great a restlessness and tossings of the members ensue, that the diseased are no more able to sleep, than if they were in a place of the greatest torture. Willis T. The Practice of Physick, Willis Treatment: Laudanum Dr. Karl-Axel Ekbom published his doctoral thesis in 1945 as a monograph entitled Restless legs a clinical study of a hitherto overlooked disease in the legs characterized by peculiar paresthesia (anxietas tibiarum), pain, and weakness and occurring in two main forms, asthenia crurum paraesthetica and asthenia crurum dolorosa. He carried out the investigation at the neurologic outpatient service of the Serafimer Hospital during the years 1943 to He was able to collect 34 severe and 120 mild cases of the paresthetic form of the disease and 15 cases of the painful form. In the following years, he gave several descriptions of restless legs as a symptom of iron deficiency (sideropenia) and, in some patients, bleeding peptic ulcers. Restless legs was found in blood donors, and a further series of reports dealt with the syndrome in subjects with, among other things, amputated limbs; this is interesting from the pathogenic point of view. Restless legs was also compared with growing pains and akathisia a symptom associated with phenothiazine treatment. Patient 1 50 yo male with 2 years of uncomfortable sensation in legs at nighttime. He notices it while watching TV around 7 PM and has to get up and walk around to get relief. It occurs almost nightly. He has trouble getting to sleep and has daytime sleepiness. Patient 1 PMH: unremarkable SH: denies etoh, denies tob FH: he has a brother with RLS Exam: Completely normal, no signs of neuropathy How do you diagnose RLS? Diagnostic Criteria Criteria A-C must be met A. An urge to move the legs, usually accompanied by or thought to be caused by uncomfortable and unpleasant sensations in the legs. These symptoms must: 1. Occur or worsen during periods of rest or inactivity such as lying down or sitting; 2. Be partially or totally relieved by movement, such as walking or stretching, at least as long as the activity continues; 3. Occur exclusively or predominantly in the evening or night rather than during the day. B. The above features are not solely accounted for as symptoms of another medical or a behavioral condition (e.g., leg cramps, positional discomfort, myalgia, venous stasis, leg edema, arthritis, habitual foot tapping). C. The symptoms of RLS cause concern, distress, sleep disturbance, or impairment in mental, physical, social, occupational, educational, behavioral, or other important areas of functioning. IRLSSG Diagnostic Criteria Four Core Symptoms are required U R G E U = Urge to move the limb(s) R = Rest worsens the sensation G = Get up & Go is Good (temporary relief with movement) E = Evening / night worsening URGE Neuroleptic-induced akathisia Fidgets Semiconscious leg jiggling Involuntary leg movements (PLM, propriospinal myoclonus at sleep onset, rhythmic movement disorder) Peripheral neuropathy Nocturnal leg cramps Vascular or neurogenic claudication Pruritus Arthritic leg discomfort Fibromyalgia Painful myopathies Varicose veins or venous insufficiency Deep vein thrombosis Fasciculations Positional discomfort Painful legs and moving toes Differential Diagnosis Patient 1 50 yo male with 2 years of uncomfortable sensation in legs at nighttime. He notices it while watching TV around 7 PM and has to get up and walk around to get relief. It occurs almost nightly. He has trouble getting to sleep and has daytime sleepiness. He meets criteria for RLS What work up would you consider? PSG? Not for RLS only, with no suspicion for underlying sleep disorder, even if they are kicking in their sleep. If BMI is elevated and snoring present, PSG would be warranted for OSA but not for RLS Work up for RLS with normal exam If not already done: Chem panel Looking for kidney disease or any other abnormality CBC Ferritin If at all suspicious for neuropathy: EMG B12, TSH, etc. Ferritin Ferritin is an acute phase reactant. If a patient has had recent fever or suffers a chronic inflammatory disorder, it is also important to measure transferrin saturation and total iron-binding capacity. Ferritin alone can be deceiving Iron status should be evaluated in all patients with RLS. In addition to ferritin, it is helpful to obtain transferrin saturation, which is the ratio of serum iron to TIBC. Supplemental iron is recommended if ferritin is < 50 ng/mL or transferrin saturation is < 20%. Treatment options for Primary RLS If ferritin below 50, iron supplementation 65 mg elemental iron with a glass of OJ or Vitamin C tablets to increase absorption GI side effects are most common and may require slow release, or iron formulated for gastric bypass patients (more easily absorbed) Treatment options continued Dopaminergic medications Alpha 2 delta ligand: Gabapentin, Horizant Clonazepam Opioids, tramadol Medical Devices for RLS Ther Clin Risk Manag. 2015; 11: 17891794. Published online 2015 Dec 3. doi: /TCRM.S /TCRM.S87208 Patient 1 Ferritin = 225, transferrin saturation normal Other labs normal How to proceed with treatment? Patient 1 50 yo male with 2 years of uncomfortable sensation in legs at nighttime. He notices it while watching TV around 7 PM and has to get up and walk around to get relief. It occurs almost nightly. He has trouble getting to sleep and has daytime sleepiness. He meets criteria for RLS What treatment is appropriate? (Audience answers) Treatment patient 1 Ropinerole.25 mg at dinner and may repeat at bedtime **TIP is to give first dose BEFORE symptoms typically begin** Patient 1 F/U 3 months and feels great! F/U 6 months later and is worried as his symptoms have worsened He takes ropinerole at dinner time and bedtime, but now while at work his legs bother him during meetings between 1-3 PM. He has also noticed it has spread to his arms. He asks you if it will keep getting worse Patient 1 What has happened? How do you help this patient? Augmentation Augmentation is worsening on RLS symptoms and earlier symptom onset during the day due to dopaminergic medications. This is thought to be due to short acting dopaminergic medications downregulating dopamine receptors 30% or so of people on dopaminergic medications can have augmentation at any time during their course Fig. 7. Proposed circadian changes in the dopaminergic output signal which could account for the circadian nature of the RLS symptoms and which could provide a biological rational for the clinical spectrum of dopamine-drug-induced augmentation. DA, dopamine; R... Christopher J. Earley, James Connor, Diego Garcia-Borreguero, Peter Jenner, John Winkelman, Phyllis C. Zee, Richard Allen Altered Brain iron homeostasis and dopaminergic function in Restless Legs Syndrome (WillisEkbom Disease) Sleep Medicine, Volume 15, Issue 11, 2014, 12881301 Treatment of augmentation Ideas? Augmentation treatment options Change to long acting dopaminergic Change class of medication to alpha 2 delta ligand Check ferritin to make sure it hasnt dropped Augmentation treatment options Neupro patch Augmentation options Gabapentin Lyrica Clonazepam Opioids/tramadol If ferritin is abnormal, iron therapy The key is to get them off of short acting dopamine agonists Patient 1 For augmentation, you decide to change him from his ropinerole to Horizant. Horizant 600 mg at dinnertime was started and he was told to stop the ropinerole. You gave him samples and told him to start it the day of the clinic visit, as well as to stop the ropinerole Patient 1 He calls the office the next day, irritated and mad, stating that he didnt get a wink of sleep last night and the Horizant isnt worth a darn and ended up taking ropinerole at 3 am just to get some damn sleep. Winkelman JW. N Engl J Med 2015;373: Medications Commonly Used for Insomnia. THIS is where the tips, tricks and know how come into play! When changing medications due to augmentation, either Overlap them OR provide short term supply of tramadol/pain pill and a sleeping pill if needed Prepare them that the next 2 weeks may be rough Behavioral Treatments Hot baths in evening Getting involved in an activity suppresses RLS activity (ie distraction) Avoiding nicotine and caffeine Some people note diphenhydramine worsens RLS Avoiding alcohol if this worsens Stretches at night Patient 2 65 yo female with myasthia gravis 3 years of urges to move legs in the evening beginning 6 PM, relieved with movement, worsened with rest, worse in the evening time. No bed partner, but currently uses CPAP for OSA Patient 2 Meds: Imuran, Mestinon, Lipitor, HCTZ Exam:Body mass index is kg/(m^2). She is awake, alert, oriented to time, place and person. Speech is fluent. NEUROLOGICAL EXAMINATION: Cranial Nerves II XII: Palpebral fissures are 9/10 mm with mild right eyelid ptosis with fatigability on the right and she does not have any diplopia. Orbicularis oculi and oris strength is 5. No fatigability, Tongue strength is normal. Motor Examination: Neck flexors and extensors are 5. Upper extremity strength is diffusely 5, lower extremity strength is diffusely 5 except, hip flexors 4+, Shoulder abductors 4+ Sensory Examination: Intact pinprick, light touch, timed vibration and proprioception. hyperesthia in the right ulnar nerve distribution. Reflexes: 2 at the biceps, brachioradialis, triceps, knee and ankle. Plantar responses are flexor. Gait and Station: Gait is normal. Patient 2 Treatment options: Patient 2 Clonazepam Gabapentin- Dopamine agonist- Patient 2 Mirapex.125 mg at dinner and.125 mg at bedtime This was effective for several months She called stating she was having break through symptoms and ultimately her Mirapex dose was raised to Mirapex.5 mg at dinner and.5 mg at bedtime Patient 2 Then she returns to clinic stating she has started compulsive internet shopping and compulsively eating resulting in weight gain What is causing the new compulsions? Patient 2 Dopamine agents can cause compulsions Not an infrequent phenomena and can be very distressful and embarrassing Patient 2 Gabapentin was then used at 100 mg tid but this resulted in sedation during the daytime Horizant was then used with improvement in her symptoms Cephalalgia.Cephalalgia Dec 6. pii: [Epub ahead of print] Susceptible genes of restless legs syndrome in migraine. Fuh JL Fuh JL 1, Chung MY 2, Yao SC 1, Chen PK 3, Liao YC 1, Hsu CL 4, Wang PJ 5, Wang YF 1, Chen SP 1, Fann CS 4, Kao LS 6, Wang SJ 7.Chung MYYao SCChen PKLiao YCHsu CLWang PJWang YFChen SPFann CSKao LSWang SJ Author information Abstract OBJECTIVE: Several genetic variants have been found to increase the risk of restless legs syndrome (RLS). The aim of the present study was to determine if these genetic variants were also associated with the comorbidity of RLS and migraine in patients. CONCLUSIONS: MEIS1 variants were associated with an increased risk of RLS in migraine patients. It is possible that an imbalance in iron homeostasis and the dopaminergic system may represent a link between RLS incidence and migraines. International Headache Society 2015. Z Gerontol Geriatr.Z Gerontol Geriatr Nov 23. [Epub ahead of print] Intravenous iron administration in restless legs syndrome : An observational study in geriatric patients. Lieske B Lieske B 1, Becker I 2, Schulz RJ 1, Polidori MC 3, Kassubek J 3, Roehrig G 4,5.Becker ISchulz RJPolidori MCKassubek JRoehrig G Author information Of the patients 7 (41 %) received 500 mg ferric carboxymaltose (FCM) and 10 patients (59 %) received iron gluconate (62.5 mg) based on the degree of iron deficiency. As assessed by the international RLS severity scale (IRLS) symptoms were recorded 3 times: at the beginning of iron therapy (t 0 ), after 2 weeks (t 1 ) and after 12 weeks (t 2 ). RESULTS: A total of 17 patients (13 female, 4 male, mean age 73.2 5.9 years) were included. The IRLS score significantly improved in all patients as shown by an average decrease from 30.2 ( 4.3) to 20.2 ( 4.7) (p < 0.001) after 2 weeks of i.v. iron treatment and to 23.2 6.6 (p < 0.001) after 12 weeks. There was a high correlation between ferritin values and the IRLS score (C 0.729, p < 0.001). The part of the IRLS referring to activities of daily living (ADL) improved from a median of 3 (scores 3-4) to 2 (scores 2-3, p = 0.001) after 2 weeks (effect size - 0.6). CONCLUSION: In this study group of geriatric outpatients i.v. administration of iron was associated with a significant improvement of symptoms inRLS as assessed by the IRLS score 2 weeks after treatment. In geriatric patients with RLS associated with iron deficiency, i.v. iron administration should be considered regarding improvement of RLS symptoms and ADL. Curr Med Res Opin.Curr Med Res Opin Nov 16:1-9. [Epub ahead of print] Effects of rotigotine on daytime symptoms in patients with primary restless legs syndrome: a randomized, placebo-controlled study. Garcia-Borreguero D Garcia-Borreguero D 1, Allen R 2, Hudson J 3, Dohin E 4, Grieger F 5, Moran K 6, Schollmayer E 5, Smit R 7, Winkelman J 8.Allen RHudson JDohin EGrieger FMoran KSchollmayer ESmit RWinkelman J Abstract OBJECTIVE: This 12 week double-blind, placebo-controlled study (ClinicalTrials.gov: NCT ) was conducted to evaluate the effects of rotigotine transdermal patch on daytime symptoms in patients with idiopathic restless legs syndrome (RLS). METHODS: Adult patients with moderate-to-severe RLS were randomized to rotigotine (optimal dose: 1-3 mg/24 h) or placebo. A modified four-assessment version (4:00 pm, 6:00 pm, 8:00 pm, and 10:00 pm) of the Multiple Suggested Immobilization Test (m-SIT) was performed at baseline and end of 4 week maintenance (EoM). Primary study outcomes were change from baseline to EoM in International Restless Legs Syndrome Rating Scale (IRLS) and in average of means for the m-SIT Discomfort Scale (m-SIT-DS) (combined average of mean values from each of the individual assessments). Secondary outcomes included average of means of Periodic Limb Movement during Wakefulness Index (PLMWI; PLM/hour) for the combination of m-SIT. Curr Med Res Opin.Curr Med Res Opin Nov 16:1-9. [Epub ahead of print] Effects of rotigotine on daytime symptoms in patients with primary restless legs syndrome: a randomized, placebo-controlled study. Garcia-Borreguero D Garcia-Borreguero D 1, Allen R 2, Hudson J 3, Dohin E 4, Grieger F 5, Moran K 6, Schollmayer E 5, Smit R 7, Winkelman J 8.Allen RHudson JDohin EGrieger FMoran KSchollmayer ESmit RWinkelman J RESULTS: A total of 150 patients were randomized and 137 (rotigotine: 92/101 [91.1%]; placebo: 45/49 [91.8%]) completed maintenance. All 150 randomized patients were assessed for efficacy. At EoM, mean change in IRLS was 9.3 with rotigotine vs 7.6 with placebo (ANCOVA, LS mean treatment difference [95% CI]: [- 2.96, 2.42]; p = ). Changes in average of means of m-SIT-DS values of each individual SIT were comparable with rotigotine (-2.68 2.31) vs. placebo (-2.62 2.61) (ANCOVA, LS mean treatment difference [95% CI]: 0.07 [-0.61, 0.75]; p = ) and comparable reductions in PLMWI were observed in both treatment groups (8.34 [- 8.50, 25.17]; p = ). Rotigotine was generally well tolerated. Application site reactions (rotigotine: 20 patients [19.8%]; placebo: 4 [8.2%]) and nausea (16 [15.8%]; 3 [6.1%]) were the most common AEs. CONCLUSIONS: Rotigotine was beneficial in improving overall RLS symptom severity (assessed by IRLS) and RLS symptom severity at various times of the day (m-SIT-DS); however, superiority to placebo was not established. Association of low ferritin with PLM in the Wisconsin Sleep Cohort. Li J Li J 1, Moore H 4th 1, Lin L 1, Young T 2, Finn L 2, Peppard PE 2, Mignot E 3.Moore H 4thLin LYoung TFinn LPeppard PEMignot E Author information Abstract OBJECTIVE: The origins of periodic leg movements (PLMs), a strong correlate of restless legs syndrome (RLS), are uncertain. This study was performed to assess the relationship between PLMs and peripheral iron deficiency, as measured with ferritin levels corrected for inflammation. METHODS: We included a cross-sectional sample of a cohort study of 801 randomly selected people (n = 1008 assays, mean age 58.6 0.3 years) from Wisconsin state employee agencies. A previously validated automatic detector was used to measure PLMs during sleep. The patients were categorized into RLS symptoms- positive and RLS symptoms-negative based on a mailed survey response and prior analysis. Analyses were performed using a linear model with PLM category above and below 15 PLM/h (periodic leg movement index, PLMI) as the dependent variable, and adjusting for known covariates, including previously associated single-nucleotide polymorphisms (SNPs) within BTBD9, TOX3/BC034767, MEIS1, MAP2K5/SKOR1, and PTPRD. Ferritin and C-reactive protein (CRP) levels were measured in serum, and ferritin levels corrected for inflammation using CRP levels. RESULTS: After controlling for cofactors, PLMI 15 was associated with low (50 ng/mL) ferritin levels (OR = 1.55, p = 0.020). The best model was found using quasi-least squares regression of ferritin as a function of PLMI, with an increase of PLM/h predicted by a decrease of 1 ng/mL ferritin (p = ). CONCLUSIONS: An association was found between low ferritin and greater PLMs in a general population of older adults, independent of genetic polymorphisms, suggesting a role of low iron stores in the expression of these phenotypes. Patients with high PLMI may require to be checked for iron deficiency. Before you marry someone, ask yourself, 'Will they be a good killing partner during the zombie apocalypse?' If you do not change direction, you may end up where you are heading. Lao Tzu Maybe all one can do is hope to end up with the right regrets. Arthur Miller